环氧乙烷灭菌的残留控制与解析工艺

结论：灭菌容易，把残留降下来难

环氧乙烷灭菌适用范围广，对不耐热材料友好，所以在医疗器械上应用很多。但它的主要工作量不在灭菌阶段，而在之后的解析阶段。

环氧乙烷及其反应产物会被材料吸附，需要通过解析（通风）过程让它们释放出来，降到可接受的水平。这个过程可能需要相当长的时间，而且时间长短取决于材料、产品结构、包装、以及解析条件。

所以规划环氧乙烷灭菌时，解析周期是需要重点估计的部分，它直接影响生产周期和在制品库存。

残留的来源与种类

环氧乙烷本身。 被材料吸附的部分。

反应产物。 环氧乙烷与材料中的某些成分反应生成的物质。

残留的分布。 不同部件、不同材料的残留水平不同。吸附强的材料残留更高、释放更慢。

包装的影响。 包装材料本身也会吸附，并且影响产品残留的释放。

残留控制的对象是产品上的残留量，而不是环境中的浓度。两者要分开看——环境浓度是职业健康问题，产品残留是使用者安全问题。

解析工艺的影响因素

温度是最有效的加速手段，但受材料耐受性限制——温度太高可能损伤产品。所以解析温度的确定是「材料耐受」与「解析效率」的平衡。

装载密度容易被忽略。 解析室里产品堆放过密，中间的产品通风不足，释放明显慢于外围。验证时应当按实际的装载密度做，并在最不利位置取样。

验证的做法

确定取样位置。 在解析室的不同位置、产品的不同部件取样。最不利位置（通风最差、材料吸附量最大的部件）要覆盖。

建立解析曲线。 在解析过程的不同时间点取样测定，画出残留随时间下降的曲线。

确定解析时间。 根据曲线确定达到可接受水平所需的时间，并留出余量。

验证最不利情形。 用最难解析的产品配置（最厚的、包装最严的、吸附量最大的材料）做验证。

确认装载方式。 规定解析时的装载密度和摆放方式。

日常监控方案。 确定日常生产中的检测频次和取样方式。

「解析曲线」是这项工作的核心产出。 有了曲线，就能回答「解析多久够」这个问题，而且在工艺调整时有判断依据。

产品设计上的配合

产品结构对解析难度影响很大：

壁厚。 厚壁件吸附多、释放慢。

材料选择。 某些材料对环氧乙烷的吸附能力明显强于其他材料。

封闭腔。 密闭的空腔既难灭菌也难解析。

多层结构。 层间的气体难以释放。

表面积与体积比。 比值大的产品释放快。

这些在设计阶段考虑，可以显著缩短解析周期。 反过来，产品定型后发现解析周期很长，改动的余地就小了，只能接受长周期或者改用其他灭菌方式。

包装设计上的配合

包装要同时满足几个要求：

透气性。 允许环氧乙烷进入和释放。

阻菌性。 灭菌后保持无菌状态。

强度。 承受灭菌过程的压力变化和运输。

密封可靠。 密封参数要经过验证。

「透气性与阻菌性」是一对矛盾，需要专门设计的材料来兼顾。包装材料选定之后，透气性对解析的影响要在验证中体现——同样的产品，包装不同，解析时间可能差别明显。

日常生产的控制

灭菌参数的记录。 每批次的完整参数。

解析条件的记录。 温度、时间、装载。

残留检测。 按确定的频次和方式做。

放行控制。 残留检测合格前不放行。

追溯。 每批产品的灭菌和解析记录可追溯。

「放行控制」是关键的控制点。 解析时间不足就放行，产品可能带着超标的残留到使用者手上，而这个问题从外观上完全看不出来。

与生物学评价的关系

环氧乙烷残留属于生物学评价要考虑的内容：

残留限值的依据。 按接触性质和接触时间确定。

与其他风险物质的叠加。 残留只是产品释放物质的一部分。

化学表征时的样品状态。 表征用的样品必须经过实际的灭菌和解析工艺，否则漏掉了这部分物质。

最后一条前面提过，这里再强调一次 ——用未灭菌的样品做化学表征，环氧乙烷相关的残留就完全测不到。

灭菌阶段的考察

虽然解析是工作量的重点，灭菌阶段本身也要确认：

预处理。 温度和湿度的调节，湿度对灭菌效果影响明显。

抽真空与置换。 空气排除的效果，与湿热灭菌的关注点类似。

气体浓度与时间。 浓度、温度、湿度、时间共同决定灭菌效果。

穿透性。 气体能否到达产品各处，特别是管腔和包装内。

装载方式。 影响气体分布。

生物指示物。 放在最难灭菌的位置验证。

「湿度」是环氧乙烷灭菌中容易被忽略的参数，但它对灭菌效果的影响很大——湿度不足时，微生物的抗力明显上升，同样的浓度和时间可能不足以灭菌。

职业健康方面

环氧乙烷对操作人员有暴露风险，相关的控制包括：

作业区的浓度监测；通风系统的设计与维护；人员防护；泄漏的检测与处置；以及排放的处理。

这部分虽然不属于产品质量范畴，但属于合规义务，规划时应当一并考虑，特别是自建灭菌设施的情形。

我们的做法

做环氧乙烷相关的验证时，我们建议按最不利情形取样——解析室通风最差的位置、产品上吸附量最大的部件。 按平均情况取样得到的数据会偏乐观。

对于化学表征的委托，我们会确认样品是否经过完整的灭菌和解析工艺。未经处理的样品测出的结果不能代表最终产品。

如果你在做环氧乙烷工艺的验证或残留评估，可以把产品结构、材料和工艺参数发过来一起讨论，或者直接联系：132 4819 8029。能力范围见服务介绍，流程见检测流程，更多内容见知识库。

English version

Conclusion. Ethylene oxide sterilisation suits a wide range of products and is kind to heat-sensitive materials, which is why it is widely used for medical devices. Its principal workload, however, lies not in sterilisation but in the aeration that follows. Ethylene oxide and its reaction products are absorbed by materials and must be released through aeration until residues fall to acceptable levels. That process can take considerable time, and the duration depends on materials, product construction, packaging and aeration conditions. When planning ethylene oxide sterilisation, therefore, the aeration period is the part most needing careful estimation, since it drives production cycle time and work in progress.

Sources and types of residue. Ethylene oxide itself, absorbed by materials. Reaction products formed between ethylene oxide and certain material constituents. The distribution of residues, which differs between components and materials, with strongly absorbing materials holding more and releasing more slowly. And the influence of packaging, which absorbs in its own right and also affects release from the product. What is controlled is residue on the product rather than concentration in the environment; the two are separate matters, environmental concentration being an occupational health question and product residue a user safety one.

Factors affecting aeration. Temperature accelerates release. Time determines the extent of release directly. Ventilation rate affects the surface concentration gradient. Material determines absorption capacity, which varies widely. Product construction matters, since thick walls, multiple layers and enclosed cavities release slowly. Packaging permeability affects release. And loading density affects air circulation. Temperature is the most effective accelerant but is limited by material tolerance, since excessive temperature can damage the product, so the aeration temperature balances tolerance against efficiency. Loading density is easily overlooked: product stacked densely in the aeration room ventilates poorly in the middle and releases markedly more slowly than at the edges. Validate at the actual loading density and sample at the least favourable position.

Validation. Determine sampling positions across the aeration room and across product components, covering the least favourable, meaning the least ventilated position and the most strongly absorbing component. Build an aeration curve by sampling at intervals through the process and plotting residue against time. Determine the aeration time from that curve, with margin. Validate the worst case using the most difficult configuration, meaning the thickest section, the tightest packaging and the most absorbing materials. Confirm the loading arrangement, specifying density and placement. And define routine monitoring, setting testing frequency and sampling method for production. The aeration curve is the core output: with it, the question of how long aeration must run can be answered, and process adjustments have a basis.

Product design. Construction strongly affects difficulty. Wall thickness governs how much is absorbed and how slowly it releases. Material selection matters, since some materials absorb ethylene oxide far more strongly than others. Enclosed cavities are hard to sterilise and hard to aerate. Multilayer constructions trap gas between layers. And surface-area-to-volume ratio determines release rate, with higher ratios releasing faster. Addressing these during design can shorten aeration substantially; discovering a long aeration period after the design is fixed leaves little room to act, and the choice becomes accepting the long cycle or changing sterilisation method.

Packaging design. Packaging must satisfy several requirements simultaneously: permeability, to let ethylene oxide in and out; microbial barrier, to maintain sterility afterwards; strength, to withstand pressure changes during the cycle and subsequent transport; and reliable sealing, with validated sealing parameters. Permeability and barrier pull against one another and require purpose-designed materials to reconcile. Once packaging is chosen, its effect on aeration must appear in validation: the same product in different packaging can differ markedly in aeration time.

Production control. Record sterilisation parameters in full for each batch. Record aeration conditions of temperature, time and loading. Test residues at the defined frequency and by the defined method. Control release, withholding product until residue testing passes. And maintain traceability of sterilisation and aeration records per batch. Release control is the critical control point: releasing product with insufficient aeration puts residues above limits into users' hands, and nothing about the product's appearance reveals it.

Relationship to biological evaluation. Ethylene oxide residues fall within biological evaluation. Residue limits are set according to contact nature and duration. Residues combine with other substances of concern, forming only part of what the product releases. And sample condition matters for chemical characterisation: samples must have been through the actual sterilisation and aeration processes, or these substances are missed entirely. That last point, made earlier, bears repeating: characterisation on unsterilised samples cannot detect ethylene oxide residues at all.

How we handle it. For ethylene oxide work we suggest sampling the worst case, meaning the least ventilated position in the aeration room and the most strongly absorbing component of the product. Sampling average positions yields optimistic data. For chemical characterisation we confirm whether samples have been through the complete sterilisation and aeration process, since untreated samples do not represent the final product.

Send us the product construction, materials and process parameters and we will work through it with you. Phone or WeChat: +86 132 4819 8029.